Displaying One Session

PARALLEL SESSION Webcast
Session Type
PARALLEL SESSION
Channel
Auditorium A
Date
21.02.2020, Friday
Session Time
09:00 - 10:00

SGLT inhibitors for type 1 diabetes - Introduction

Session Type
PARALLEL SESSION
Date
21.02.2020, Friday
Session Time
09:00 - 10:00
Channel
Auditorium A
Lecture Time
09:00 - 09:20

Abstract

Background and Aims

Since the majority of people with T1D do not achieve target A1cs (<7 or 6.5%) and more than 2/3 of the patients with T1D are getting overweight or obese, it is important to find adjunctive therapies for patients with T1D, which might help achieving target A1cs without any increase in weight[1]. Several molecules (like metformin, GLP analogs, coleselvelam, and DPP-4 inhibitors) have been evaluated as adjunctive therapeutic options for T1D[2],[3]. Unfortunately, none of them have been successful in significantly improving glucose control or weight loss; and thus, are not approved for their use in patients with T1D. The only FDA-approved option for adjunctive therapy for patients with T1D is pramlintide, which is rarely used because of GI side-effects and risk of severe hypoglycemia[4].

Background and Aims

Since the majority of people with T1D do not achieve target A1cs (<7 or 6.5%) and more than 2/3 of the patients with T1D are getting overweight or obese, it is important to find adjunctive therapies for patients with T1D, which might help achieving target A1cs without any increase in weight[1]. Several molecules (like metformin, GLP analogs, coleselvelam, and DPP-4 inhibitors) have been evaluated as adjunctive therapeutic options for T1D[2],[3]. Unfortunately, none of them have been successful in significantly improving glucose control or weight loss; and thus, are not approved for their use in patients with T1D. The only FDA-approved option for adjunctive therapy for patients with T1D is pramlintide, which is rarely used because of GI side-effects and risk of severe hypoglycemia[4].

Methods

SGLT 2 inhibitors have been successfully used for patients with T2D with a significant reduction in cardiovascular disease and renal failure. Since this class of drugs have insulin-independent effect and in early phase 1 and 2 clinical trials for patients with T1D showed significant benefits. Several Phase 3 trials were reported in the last two years with SGLT 1 and/or 2 inhibitors used adjunctively with insulin in patients with T1D[1]. DEPICT[2] (dapagliflozin) in T1D showed improvement in A1c, Time-in-Range (TIR), and weight loss with a small but significant increase in diabetic ketoacidosis (DKA). The second trial (replicating real-life use) using a dual SGLT 1 and 2 inhibitor (inTandem 3-Sotagliflozin in T1D)[3] showed significant reduction in A1c, hypoglycemia, especially severe (<55mg/dL) and weight loss. The other two large trials done in the USA and Europe using Sotagliflozin (in Tandem 1 and in Tandem 2) also showed similar results[4],[5]. Similarly, there was a small, but significant, increase DKA, which is now known with all SGLT 2 inhibitors. It’s important to keep in mind that the background risk of DKA is ~5% in the USA (T1D Exchange data—see reference 3) and is increasing significantly in Europe with or without the use of these medications[1]. Lastly, EASE 2 and 3 trials[2] using Empagliflozin in T1D and showed similar benefits and risks like Dapa and Sota except the authors recommended a smaller dose of 2.5mg a day to be considered for T1D (due to no increase in DKA risk, but efficacy on A1c was about 50%) based on a small sample size in EASE 3.

Methods

SGLT 2 inhibitors have been successfully used for patients with T2D with a significant reduction in cardiovascular disease and renal failure. Since this class of drugs have insulin-independent effect and in early phase 1 and 2 clinical trials for patients with T1D showed significant benefits. Several Phase 3 trials were reported in the last two years with SGLT 1 and/or 2 inhibitors used adjunctively with insulin in patients with T1D[1]. DEPICT[2] (dapagliflozin) in T1D showed improvement in A1c, Time-in-Range (TIR), and weight loss with a small but significant increase in diabetic ketoacidosis (DKA). The second trial (replicating real-life use) using a dual SGLT 1 and 2 inhibitor (inTandem 3-Sotagliflozin in T1D)[3] showed significant reduction in A1c, hypoglycemia, especially severe (<55mg/dL) and weight loss. The other two large trials done in the USA and Europe using Sotagliflozin (in Tandem 1 and in Tandem 2) also showed similar results[4],[5]. Similarly, there was a small, but significant, increase DKA, which is now known with all SGLT 2 inhibitors. It’s important to keep in mind that the background risk of DKA is ~5% in the USA (T1D Exchange data—see reference 3) and is increasing significantly in Europe with or without the use of these medications[1]. Lastly, EASE 2 and 3 trials[2] using Empagliflozin in T1D and showed similar benefits and risks like Dapa and Sota except the authors recommended a smaller dose of 2.5mg a day to be considered for T1D (due to no increase in DKA risk, but efficacy on A1c was about 50%) based on a small sample size in EASE 3.

Results

More recently, a meta-analysis of inTandem studies showed significant reduction in hypoglycemia (<70mg/dL) and severe hypoglycemia (defined as <54mg/dL)[1]. SGLT inhibitors have been approved in Europe and Japan as adjunctive therapy for patients with T1D whose BMI is >27kg/m2 and whose insulin requirements are 0.5 units/kg/day. In the USA, no SGLT inhibitor has been approved for patients with T1D and the FDA has issued a complete response letter (CRL) for both sota- and dapagliflozin. If and when these drugs are approved for patients with T1D in the USA, the risk of DKA will need to be mitigated by proper education for patients and providers following the STICH and STOP DKA protocols[2],[3],[4].

Results

More recently, a meta-analysis of inTandem studies showed significant reduction in hypoglycemia (<70mg/dL) and severe hypoglycemia (defined as <54mg/dL)[1]. SGLT inhibitors have been approved in Europe and Japan as adjunctive therapy for patients with T1D whose BMI is >27kg/m2 and whose insulin requirements are 0.5 units/kg/day. In the USA, no SGLT inhibitor has been approved for patients with T1D and the FDA has issued a complete response letter (CRL) for both sota- and dapagliflozin. If and when these drugs are approved for patients with T1D in the USA, the risk of DKA will need to be mitigated by proper education for patients and providers following the STICH and STOP DKA protocols[2],[3],[4].

Conclusions

Finally, the use of SGLT inhibitors as adjunctive therapy for T1D may allow many more patients to achieve target A1cs without any further weight gain and may in fact have long-term cardiovascular and renal benefits as have been shown in patients with T2D.

[1] Garg SK, et al. Diabetes Technol Ther. 2019 Feb;21: 66-72. PMID: 30657336.

[2] Garg et al. Endocrine Practice, 2013;19:19-28.

[3] Garg SK et al, Diabetes Obesity and Metabolism, 2011; 13:137-43.

[4] Weyer et al. Diabetes Care 2003; 26:3074–3079.

[5] Garg SK. Diabetes Technol Ther, 19 (10):549-551, 2017. PMID: 28891680.

[6] Dandona P et al. Lancet DE 2017; 5:864-876.

[7] Garg SK, et al. N Engl J Med. 2017;377:2337-2348.

[8] Buse JB, Garg SK et al. Diabetes Care 2018;41:1970−80.

[9] Danne T, et al. Diabetes Care 2018;41:1981−90.

[10] Zhong et al. Diabetes Care 2018;41:1870.

[11] Rosenstock J, et al. Diabetes Care. 2018 Dec;41(12):2560-2569. PMID: 30287422.

[12] Danne T, Garg SK, et al. Diabetes Care Jun 2019 (42). PMID: 31335194.

[13] Garg SK, et al. Diabetes Technol Ther. 2018 (20): 571-575. PMID: 30129772.

[14] Danne T, Garg SK, et al. Diabetes Care Jun 2019 (42). PMID: 31335194.

[15] Goldenberg RM, et al. Diabetes Obes Metab. Jun 2019. ePub ahead of print. PMID: 31183975.

Conclusions

Finally, the use of SGLT inhibitors as adjunctive therapy for T1D may allow many more patients to achieve target A1cs without any further weight gain and may in fact have long-term cardiovascular and renal benefits as have been shown in patients with T2D.

[1] Garg SK, et al. Diabetes Technol Ther. 2019 Feb;21: 66-72. PMID: 30657336.

[2] Garg et al. Endocrine Practice, 2013;19:19-28.

[3] Garg SK et al, Diabetes Obesity and Metabolism, 2011; 13:137-43.

[4] Weyer et al. Diabetes Care 2003; 26:3074–3079.

[5] Garg SK. Diabetes Technol Ther, 19 (10):549-551, 2017. PMID: 28891680.

[6] Dandona P et al. Lancet DE 2017; 5:864-876.

[7] Garg SK, et al. N Engl J Med. 2017;377:2337-2348.

[8] Buse JB, Garg SK et al. Diabetes Care 2018;41:1970−80.

[9] Danne T, et al. Diabetes Care 2018;41:1981−90.

[10] Zhong et al. Diabetes Care 2018;41:1870.

[11] Rosenstock J, et al. Diabetes Care. 2018 Dec;41(12):2560-2569. PMID: 30287422.

[12] Danne T, Garg SK, et al. Diabetes Care Jun 2019 (42). PMID: 31335194.

[13] Garg SK, et al. Diabetes Technol Ther. 2018 (20): 571-575. PMID: 30129772.

[14] Danne T, Garg SK, et al. Diabetes Care Jun 2019 (42). PMID: 31335194.

[15] Goldenberg RM, et al. Diabetes Obes Metab. Jun 2019. ePub ahead of print. PMID: 31183975.

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SGLT2 in type 1 diabetes – Efficacy

Session Type
PARALLEL SESSION
Date
21.02.2020, Friday
Session Time
09:00 - 10:00
Channel
Auditorium A
Lecture Time
09:20 - 09:40

Abstract

Background and Aims / Part 1

Several issues still exist with present day insulin therapy, with insufficient matching of insulin profiles to insulin needs resulting in many people with type 1 diabetes not reaching HbA1c targets and suffering from recurrent hypoglycemia. This risk of hypoglycemia, in particular nocturnal hypoglycemia, impacts on quality of life and contributes to weight gain via defensive snacking. Intuitively, clinicians have been experimenting with non-insulin adjunctive therapies in type 1 diabetes, typically by introducing agents used in people with type 2 diabetes. As such, metformin has been used, with however, few and rather discouraging data on long term effects. Recently, novel agents, like GLP-1 receptor agonists and SGLT2/SGLT1-2 inhibitors have been or are being tested as adjunct therapies, with interesting results.

Conclusions / Part 4

In Europe, dapagliflozin and sotagliflozin have been approved for use in people with T1D as low doses and provided the user has a BMI>27kg/m2 and receives education on how to prevent evolution to diabetic ketoacidosis.

In the meantime, real world evidence on use of SGLT inhibitors is accumulating and allows a better characterization of the optimal patient profile to use these agents in as well as design of mitigation strategies for diabetic ketoacidosis.

Evidence and clinical experience will be discussed.

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Experience with risk mitigation using SGLT inhibitors in type 1 diabetes

Session Type
PARALLEL SESSION
Date
21.02.2020, Friday
Session Time
09:00 - 10:00
Channel
Auditorium A
Lecture Time
09:40 - 10:00

Abstract

Background and Aims / Part 1

Experiences with adjunct therapy with SGLTinhibitors in type 1 diabetes, both, during the regulatory trials as well as through off-label use have contributed to recent international DKA risk mitigation consensus.

Methods / Part 2

These recommendations have been the basis for a package of mandatory patient and provider information, which has been developed by the pharmaceutical company ((https://www.frx-schulungsmaterial.de. Recently a structured, product independent education program “KetoAWARE” for DKA risk mitigation was developed by FIDAM (https://www.fidam.de/ketoaware) together with international experts. It can be downloaded and used for individual or group-based educational sessions for adult users of SGLT inhibitors. It is currently available in German and English and ten more languages are coming soon. In addition, a Smartphone App will be developed by the end of the year. This App aims at improving ongoing support for SGLT users regarding DKA management in daily life.

Results / Part 3

Real-world data from the German DPV-Registry show that the approval of SGLTinhibitors for certain patients with type 1 diabetes are likely to lead to considerable use.

Conclusions / Part 4

Such real-world data will be helpful to monitor the development of acute complications like hypoglycemia and DKA during adjunct therapy with SGLT in patients with type 1 diabetes.

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